U.S.Department ofHealth and HumanServicesFood and DrugAdministration

Center forDrug Evaluation and Research(CDER)

ClinicalMedicalApril 2015

Additionalcopiesareavailablefrom:OfficeofCommunications

DivisionofDrugInformation,WO51,Room220110903NewHampshireAve.

SilverSpring,MD20993-0002Phone:301-796-3400;Fax:301-847-8714

U.S.Department ofHealth and HumanServicesFood and DrugAdministration

Center forDrug Evaluation and Research(CDER)

ClinicalMedicalApril 2015

TABLE OFCONTENTS

I.INTRODUCTION...... 1

II.BACKGROUND...... 1

III.ABUSE-DETERRENTPRODUCTS...... 3

IV.PREMARKETSTUDIES...... 4

A.LaboratoryManipulationand Extraction Studies(Category 1)...... 6

B.PharmacokineticStudies(Category2)...... 8

C.ClinicalAbuse PotentialStudies(Category 3)...... 9

1.Blinding...... 10

2.Pre-qualificationPhase...... 10

3.AssessmentPhase...... 11

4.Subjects...... 11

5.Route ofAdministration,DoseSelection,ManipulationMode, and SamplePreparation...... 12

6.OutcomeMeasures and DataInterpretation...... 12

7.DataInterpretation...... 13

8.StatisticalAnalysis...... 14

a.Background...... 14

b.Primaryanalyses...... 15

c.Secondaryanalyses...... 15

d.Multiplicity...... 17

V.POSTMARKETSTUDIES(CATEGORY 4)...... 17

A.FormalStudies...... 18

1.GeneralCharacteristics...... 18

2.StudyDesignFeatures...... 19

B.SupportiveInformation...... 21

VI.LABELING...... 22

VII.ADDITIONALRESEARCHNEEDS...... 25

Abuse-DeterrentOpioids—EvaluationandLabelingGuidanceforIndustry1

I.INTRODUCTION

Thisguidance explains FDA’scurrent thinking about the studiesthatshould be conducted todemonstrate that agivenformulationhasabuse-deterrentproperties.Theguidance makesrecommendationsabouthowthose studies should be performedandevaluatedanddiscusses howto describe those studiesandtheir implications in productlabeling.

Thisguidance is intended to assistsponsorswhowish to develop opioid drugproducts withpotentiallyabuse-deterrentpropertiesand is not intended to applyto products thatare not opioidsoropioid productsthat do not have the potential for abuse.

Thisguidance alsodoesnot addressissuesassociatedwith the development or testingofgenericformulations of abuse-deterrent opioid products. FDA intends to addressthat topicin oneormore futureguidance documents.

Ingeneral,FDA’sguidance documents do not establish legallyenforceableresponsibilities.Instead,guidancesdescribe the Agency’scurrent thinkingon atopic and should be viewedonlyasrecommendations,unlessspecific regulatoryorstatutoryrequirements are cited.Theuseofthe wordshould in Agencyguidances means thatsomethingis suggestedor recommended, butnot required.

II.BACKGROUND

Prescription opioid productsareanimportant component of modernpainmanagement.However,abuseand misuseof these products have created aserious andgrowingpublichealthproblem. One potentiallyimportantsteptowardsthe goal ofcreatingsaferopioid analgesicshas

1ThisguidancehasbeenpreparedbytheDivisionofAnesthesia,Analgesia,andAddictionProducts,theOfficeofRegulatoryPolicy,theOfficeofSurveillanceandEpidemiology,theOfficeofBiostatistics,andtheControlledSubstanceStaffintheCenterforDrugEvaluationandResearch(CDER)attheFoodandDrugAdministration.

been the development ofopioids thatare formulated to deter abuse.FDA considers thedevelopment of these products a high publichealth priority.

Because opioid productsare often manipulated forpurposes ofabusebydifferent routes ofadministration orto defeatextended-release (ER)properties, most abuse-deterrenttechnologiesdeveloped to dateare intended to make manipulation more difficult orto make abuse ofthemanipulatedproductlessattractive or lessrewarding. It should be noted that these technologieshave notyetproven successful atdeterringthemost commonform of abuse—swallowing anumber of intact capsules or tablets to achievea feelingof euphoria. Moreover, the factthat aproducthasabuse-deterrentpropertiesdoes not mean that thereis no risk of abuse.It means,rather,that therisk ofabuseis lower than it would be withoutsuchproperties.Because opioidproducts must in the end be able to deliver theopioid to the patient,theremayalways besomeabuse of theseproducts.

For purposes ofthis guidance,abuse-deterrentpropertiesare definedas those propertiesshownto meaningfullydeter abuse, even iftheydo not fullypreventabuse.The term abuseis definedas the intentional,non-therapeutic useofadrugproduct or substance,evenonce, to achieve adesirable psychological or physiologicaleffect.2Abuse is not the same asmisuse, whichrefers tothe intentionaltherapeutic useofadrugproduct inaninappropriate wayand specificallyexcludes the definition ofabuse.3Thisguidance uses the termabuse-deterrentrather thantamper-resistantbecausethe latter termrefers to, oris used in connectionwith,packagingrequirementsapplicable tocertainclasses ofdrugs, devices,andcosmetics.4

The science ofabuse deterrence is relativelynew,and both the formulationtechnologiesand theanalytical,clinical,andstatisticalmethodsfor evaluatingthose technologiesare rapidlyevolving.Based on theevolvingnatureofthe field,FDA intends to take aflexible, adaptive approach tothe evaluationand labelingofpotentiallyabuse-deterrentproducts.Methods for evaluatingtheabuse-deterrentproperties of new molecular entities mayhaveto beadaptedbased on thecharacteristics ofthoseproducts and the anticipatedroutes ofabuse.Thedevelopment of anabuse-deterrent opioid product should be guidedbytheneed to reduce theabuse known orexpected to occur with similar products.

BecauseFDAexpectsthat the marketwillfoster iterative improvements inproductswithabuse-deterrentproperties, noabsolute magnitude ofeffectcanbe setforestablishingabuse-deterrentcharacteristics. As aresult, FDA intends to consider thetotalityof the evidence whenreviewingthe results of studiesevaluatingtheabuse-deterrentproperties ofaproduct.

2SmithSM,DartRC,KatzNP,etal.2013.Classificationanddefinitionofmisuse,abuse, andrelatedeventsinclinicaltrials:ACTTIONsystematicreviewandrecommendations.Pain,154:2287-2296.

3Ibid.

4FDA’scurrentGoodManufacturingPracticeregulationsincludetamper-evidentpackagingrequirements.See21CFR211.132.Therearealsorequirementsforchildresistant“specialpackaging”underthePoisonPreventionPackagingActandregulationsadoptedbytheConsumerProtectSafetyCommissioner(CPSC)in16CFR1700.

AswithallNDA products, FDA intends to consideropioids withabuse-deterrentpropertieswithin thecontext of available therapy.The standardagainstwhicheachproduct’sabuse-deterrentpropertiesareevaluatedwilldepend on the range of abuse-deterrentandnon-abuse-deterrentproducts on themarketat thetimeof thatapplication.5

Abuse-deterrent properties cangenerallybe established onlythroughcomparison to anotherproduct.

FDA encourages additional scientific andclinicalresearchthatwill advancethe developmentandassessment ofabuse-deterrenttechnologies.

FDA believes it is critical to address the problemofopioid abuse while seekingto ensure thatpatients in painhave appropriate access to opioid products.Moreover, it is importantthatopioids withoutabuse-deterrentpropertiesremainavailable forusein someclinicalsettings. Forexample,patients in hospice care andwith difficultyswallowingmayneedaccess to opioidproductsthatare in solution or thatcan becrushed.

The followingsection describes the categoriesof abuse-deterrentproducts. The premarketandpostmarketstudiesthat should be performed to assess the impact ofapotentiallyabuse-deterrentproduct are discussed insubsequentsections.Finally,information is providedabout labelingforabuse-deterrentproducts.

III.ABUSE-DETERRENTPRODUCTS

Opioidproductscan beabused in a number ofways. For example, theycan be swallowedwhole,crushedandswallowed,crushedand snorted, crushedand smoked, or crushed,dissolvedandinjected. Abuse-deterrenttechnologies shouldtargetknown orexpected routes of abuserelevant to theproposedproduct. As ageneralframework,abuse-deterrentformulationscancurrentlybecategorizedasfollows:

1.Physical/chemical barriers – Physicalbarrierscanpreventchewing,crushing,cutting,grating,or grindingofthe dosage form.Chemicalbarriers, such asgellingagents,canresistextraction oftheopioid usingcommonsolvents like water,simulatedbiologicalmedia,alcohol, orotherorganic solvents.Physicalandchemicalbarrierscan limit drugrelease followingmechanicalmanipulation, orchangethe physicalform ofa drug,renderingit less amenableto abuse.

2.Agonist/antagonistcombinations– An opioid antagonistcanbe added to interfere with,reduce,or defeat theeuphoria associatedwith abuse. The antagonist can be sequesteredandreleasedonlyuponmanipulation oftheproduct.Forexample, adrug productcanbe

5ForguidanceontheevaluationofabusepotentialforpurposesoftheControlledSubstancesAct(CSA), werefersponsorstoFDA’sdraftguidanceforindustryAssessmentofAbusePotentialofDrugs.Thisguidanceisavailable at:

formulatedsuchthat thesubstance that acts asanantagonist is not clinicallyactive whenthe product is swallowed,but becomesactive ifthe product is crushedandinjected orsnorted.

3.Aversion – Substances can be added to theproductto produce anunpleasanteffect ifthedosage form is manipulated oris usedat ahigherdosage thandirected.For example, theformulationcanincludea substance irritatingto the nasalmucosa ifground andsnorted.

4.Delivery System(includinguseof depotinjectable formulationsand implants)– Certaindrugrelease designs orthe method ofdrugdeliverycan offer resistance toabuse.Forexample,sustained-release depotinjectableformulation ora subcutaneous implant maybe difficult to manipulate.

5.Newmolecularentities and prodrugs– The properties ofa new molecular entity(NME)orprodrugcouldincludethe need for enzymatic activation,differentreceptor bindingprofiles,slower penetration into the central nervous system, orother noveleffects.Prodrugswithabuse-deterrentpropertiescould providea chemicalbarrier tothein vitroconversion to the parentopioid, which maydeterthe abuse ofthe parent opioid.Newmolecular entitiesandprodrugsare subject to evaluation of abuse potentialfor purposesofthe ControlledSubstancesAct(CSA).

6.Combination– Two or more oftheabove methodscould be combined to deter abuse.

7.Novelapproaches– Thiscategoryencompasses novel approaches or technologiesthatare not captured in theprevious categories.

IV.PREMARKETSTUDIES

Firstandforemost,anystudiesdesigned to evaluate the abuse-deterrentcharacteristics of anopioid formulationshould bescientificallyrigorous. Importantgeneralconsiderationsfor thedesign ofthese studiesinclude the appropriateness ofpositivecontrols6andcomparator drugs,outcome measures,dataanalyses to permit a meaningfulstatistical analysis, andselection ofsubjectsfor the study.

The evaluation ofanabuse-deterrentformulation should take into consideration the knownroutes of abusefor the non-abuse-deterrentpredecessor or similar products,aswellasanticipatethe effectthat deterringabusebyone route mayhaveon shiftingabuse toother, possiblyriskierroute. Forexample, ifaproduct is known to beabused usingnasal andintravenous routes,developingdeterrentpropertiesfor thenasal routein the absence of deterrentpropertiesfor theintravenousroute risks shiftingabusersfrom thenasal to the intravenous route, which isassociatedwith agreaterriskfor the spread ofinfectious diseases.

Another conceptthat should be considered is whether the deterrenteffects can be expected tohave a meaningful impact on the overallabuse ofthe product. For example, immediate-release(IR) opioid andacetaminophencombination products are predominantlyabused usingthe oral

6Forpurposesofthisguidance,apositivecontrolisanopioiddrugproductordrugsubstanceexpectedtoresultinapredictableopioiddruglikingeffectandhasaknownpotentialfor,orhistoryof,abuse.

route. Demonstratinga deterrenteffectbythenasal route maynot meaningfullyreduce overallabuse oftheproduct.

FDA is committed to retaininga flexible,adaptiveapproach toevaluatingpotentiallyabuse-deterrent opioid drugproducts.This flexibilityisintended to permit asponsorto tailor thedevelopmentprogram to suit the abuse-deterrentcharacteristics of their product and the routes ofabuse for that product.The adaptiveaspect is intended to permit asponsorto take intoconsideration therelevant products on the marketat thetimetheyare developingtheir product,so thatappropriate non-abuse-deterrentandabuse-deterrentcomparators can be used. Forexample,for someproposed products theappropriate comparator maybeaconventionalformulation. However, if thereare similar approved productswithabuse-deterrentpropertiesdescribed in labeling, theappropriatecomparatorshould beoneofthose abuse-deterrentproducts.

The followingsections describe three categoriesof premarketstudies.Although, ingeneral,anydevelopmentprogramforstudyingabuse-deterrenttechnologies should include data from allthree categoriesof studies,there maybeexceptions.For example, a formulationwith asequesteredantagonist mayintentionallybeformulated not to resistcrushing, so testingthesyringeabilityoftheproduct maynot be relevant. In most cases,however,toobtain a fullandscientificallyrigorous understandingofthe impactofatechnologyor technologies on aproduct’sabuse potential, data fromeach ofthefollowingthreecategoriesof premarketstudiesare appropriate:

1.Laboratory-based in vitromanipulationandextractionstudies(Category1)

2.Pharmacokinetic studies(Category2)

3.Clinicalabuse potentialstudies (Category3)

The results ofCategory1studies mayinfluence the designofCategory2 pharmacokineticstudiesand Category3 clinicalabuse potentialstudiesbysuggestingthemethods ofmanipulationthatwouldyield thegreatest releaseofopioid. The results ofCategory2 studiesmayinfluence theneedforCategory3 studies ofclinicalabuse potential and the designsandgoals ofthese studies. For example, ifthe extended-release characteristicsof anabuse-deterrentopioid formulation cannot be defeatedand the pharmacokinetic profile remainsunchangedfollowingoral or nasaladministration ofthe manipulatedproduct, oral andnasalstudies of abusepotential maynot be necessary.

Additionalstudies(i.e., Category4 studies) analyze postmarketdata to assess the impact of anabuse-deterrentformulation on actualabuse. Nonclinical drugdiscriminationstudiesare usefulin the evaluation oftheabuse potential ofa drug,but their utilityin predictingthe impact ofabuse-deterrentproperties on humanbehavior hasnot been established.7

7SeeFDAdraftguidanceforindustry,AssessmentofAbusePotentialofDrugssee

A.LaboratoryManipulation and ExtractionStudies(Category 1)

The goal of laboratory-based Category1 studies should beto evaluate theease withwhich thepotentiallyabuse-deterrentproperties ofaformulationcan be defeatedor compromised.Thisinformation should be usedwhen designingCategory2and Category3 studies. These studiesare critical to the understandingofproductcharacteristicsand performance.8

Methodologically, thesestudies should be designedwithknowledge ofthephysicochemicalproperties oftheproductand the methodsavailable to abusers to manipulatethe productandshould be conducted on the to-be-marketedformulation. Sponsors shouldconsider both themechanismsbywhichabuserscanbe expected toattempt to deliberatelyovercome theabuse-deterrentpropertiesofthe productas well as thewaysthatpatientsmayalterthe formulation(unintentionallyor intentionally) thatchange therateor amount ofdrug released(e.g., dosedumpingmayoccurwhen takingtheproduct withalcohol or when theproduct is cut,chewed,orcrushed). Testingshouldprovide informationsufficient to fullycharacterize the product’s

abuse-deterrentproperties,includingthe degree of effortrequired to bypassor defeat thoseproperties. In somecases,whendesigningin vitro studies, it maybeuseful to obtaininformationfromprescription opioid abusersabout howtheywouldmanipulate and abuse anabuse-deterrentproduct.

Invitrostudies should assess various simple andsophisticatedmechanicalandchemicalways adrugcould be manipulated,suchasby(1) defeatingorcompromisingthecontrolledrelease of anopioid fromERformulationsfor purposes ofabuse bydifferentroutes ofadministration;(2)preparinganIRformulationfor alternativeroutesof administration; or (3)separatingtheopioidantagonist, if present, from theopioid agonist, thus compromisingthe product’sabuse-deterrentproperties. Thegoal ofthese studies is to manipulate the product to thepoint of defeatingitsabuse-deterrentproperties. Once this goal is achieved, it is no longer necessaryto continueexperiments usingmoresophisticatedmethods.For example, if90%oftheopioid can beextractedundera set ofconditions in 10 minutes,there is no need to test the same conditionfor30 minutes.

The testproduct should be compared to appropriate comparator products for ease of mechanicalmanipulation. The abilityto crush,cut,grate,or grind theproduct formulation usingreadilyavailable itemssuchas spoons, cutters,and coffee grinders should beassessed. Particularattention should be givento particle size distributionfollowingeach modeof physicalmanipulationbecause particlesizemayinfluence the rate ofopioid extractionfrommanipulatedproduct. The effect ofheat andcold on mechanicalmanipulation should also be studied.

Extractabilityand solubilitystudies should be designed to determine whether anyoftheformulationcomponentsmight bedifferentiallysolubilized andextracted,allowingan abuserto

8Thistopichasbeendiscussed atmeetingsoftheAnestheticLife SupportDrugsAdvisoryCommitteeandtheDrugSafetyRiskManagementAdvisoryCommittee(NDA022272,OxyContin,May5,2008,andSeptember24,2009).AdditionalinformationonthesemeetingsisavailableonFDA’swebsiteatthefollowinglocation: DrugProductsAdvisoryCommittee/UCM187082.pdf.

bypass the drug’sabuse-deterrentproperties. In addition to extractionand solubilitystudies,anassessment should bemadeto determine iffree-baseopioid can be precipitatedfrom solution bypH adjustment. After establishinghowaproductcould be manipulated,chemicalextraction oftheopioid from the intactand the manipulated product should be assessedand compared toopioid extractionfrom the selected intact and similarlymanipulatedcomparator products.

The easeofextractingtheopioid from the intact and manipulatedproduct should be determinedusingavarietyofsolvents thatare commonlyavailable (e.g.,water, vinegar, ethanol,isopropanol,acetone,mineralspirits) and thosethat have potentiallyrelevant solventcharacteristics(e.g.,pH,polarity,protic vs.aprotic).Theeffects of time,temperature,pH,andagitation on solvent extraction should also be determined.For products containingmore thanonedrugsubstance,extractabilityand solubilitystudies should be designedto determine whetheranyoftheactive ingredientsmight be differentiallysolubilized andextracted.Samplingtimesshould start early(e.g.,30seconds) andcontinueuntil atleast 80%oftheopioid hasbeenreleased, or12 hours has beenreached.The in vitro drug-releasecharacteristics ofthe intactandmanipulatedproduct should also be compared usingadiscriminatoryand robust dissolutionmethod.

Inaddition to the generalevaluation ofthe effectsof physicalandchemicalmanipulation on theproduct,thereare important route-specific data that should be generated, as follows:

  • For aproduct with potential for abuse bythenasalroute, the particle sizedistributionfollowingattempted manipulation byvarious methods should be established,and themethodthatprovides thesmallestparticle sizeshould be used in subsequent studies.
  • For aproduct with potential for abuse bysmoking,the amount ofdrugproducedbyvaporizationattemperaturesencompassingtherangefrom themeltingpoint ofthe activeingredient to its degradation point should be determined.Appropriatecontrols,suchaspure active ingredient, both in saltandfree-baseform should be included in theseassessments.
  • For aproduct with potential for abuse byinjection, the amount ofopioid thatcan beobtained in a syringe should be based on studiesof intactandmanipulated test productandcomparator(s) using smallvolumes of water (5-10 mL)atroomtemperature andat90° C – 95° C withandwithoutagitation. Extractiontimes should range from 30 secondsto 30 minutes. The amount ofopioid extracted, thevolumeofsolution collectedand theviscosityofthe samples should be recorded.Theabilitytoget thesampleinto a syringeand expel the sample usingneedles ofvariousgauges should alsobe explored.

The followingexamplesillustrate thekinds of outcomesthat in vitrostudies should evaluate.

1.Characteristics oftheproduct bycrushing,grindingor melting, orbychangingthe intactformulation usingothermethodsthatwould limitnasaladministration ofthe manipulatedproduct,and/or that would limit dissolution ofthemanipulatedproductandincorporationinto a solventthatcouldthen be injectedbyintravenous or subcutaneous routes.

2.Quantityoftheopioid extracted from the productfollowingthevarious methods attemptedthatcould be usedfor injection byintravenous orsubcutaneousroutesanda description ofanybarriers resultingfrom attemptsat dissolutionfor drawingthedruginto a syringe.

3.Quantityofopioid antagonist released from anagonist/antagonist combination when it ismanipulatedfor administrationbyingestion, nasal administration, or injection.

4.Quantityofopioid product followingin vitro manipulation ofthe prodrug.

B.Pharmacokinetic Studies(Category 2)

The goal oftheclinicalpharmacokinetic studies,Category2, should beto understand thein vivoproperties oftheformulationbycomparingthe pharmacokinetic profiles ofthe manipulatedformulationwith the intactformulationandwithmanipulatedandintactformulations ofthecomparator drugs through oneor moreroutes of administration.Eventhough thesame routes ofadministration should be studiedfor the new product andcomparators, if specific circumstancesprevent this approach, thestudydesign should bediscussedwithFDA. The method ofmanipulationusedfor the pharmacokinetic studies should be based on themethodsexploredduringin vitrotestingthat can be expected to result in the greatest drugrelease.The routes ofadministrationchosen should be relevant to theproposed product,and likelywill bebased onwhat is knownabout theabuse of similar products.Note that,for some developmentprograms,it maybe preferable tocombine measures of pharmacokinetic parametersforCategory3 studies,in whichcase separateCategory2 studiesmaynot be necessary.

Ingeneral, the pharmacokinetic profile for theoral route of administration should be studied.Appropriate studysubjects for Category2 studiesinclude healthyvolunteersas longasnaltrexone is used to block the pharmacodynamiceffects oftheopioids.

Dependingon theproduct, it maybe important toevaluate the pharmacokinetic profile forthenasalroute ofadministrationaswell. For nasal pharmacokinetic studies, itis important to weighthe risk to the subject based on the excipients in the formulation.Onlysubjectswith ahistoryofnasalabuse ofopioids should be recruitedfor these studies.Aswith theoral route ofadministration, it maybe possibleto combine the pharmacokineticassessmentand thepharmacodynamic assessment in one clinical abuse potential studywith samplingfor thepharmacokineticanalysis.

Relevantpharmacokinetic parameters fortheopioid drugand anypsychoactive metabolitesthatshould be measured in these studiesinclude the following.

  • Maximum concentration(Cmax)
  • Time to maximumconcentration(Tmax)
  • Area underthecurve(AUC0-tandAUC0-∞)
  • RelevantpartialAUC, includingearlytimepoints suchasAUC0-30minutes or AUC0-2hours, the period oftimewhenCmaxis expected
  • Terminaleliminationhalf-life (T1/2)

Traditionalpharmacokinetic studydesigns shouldbe employed(e.g.,crossover designs),and theresults should be analyzed usingbioequivalencemethods.The rate of riseofdrugconcentrationshould be assessed whenpossible because it is thought to contribute to differential abusepotentialamongdrugs,formulations,androutesofadministration.9 Tosupportthese analyses, itis important to have specimencollectionandanalysis timepoints sufficient to cover the onset,peak,andoffset oftheeffects ofbothIRandERformulations, in both the intactandmanipulatedconditions. Inaddition, these dataare necessarytocalculate therelevantpartialarea underthecurve,which shouldcapture thetimeto maximumconcentration oftheopioid.

Iffoodandalcoholalter the pharmacokinetic parameters ofthe formulation,data should beprovided to characterize thoseeffects.10 If food significantlyincreases systemicexposureoftheintactformulation, the underlyingmechanismfor the foodeffect should beestablishedbyassessingwhether the effect is based on thedrugsubstanceortheformulationandwhether theeffect is presentwith intact productas well aswithmanipulatedproduct. When food is expectedto increaseexposure,subsequentabuse potential studies ofthe oralroute should be conducted inthe fedstate to maximizethe potentialsystemic exposure.

Inaddition to the pharmacokinetic profile oftheopioid, for agonist/antagonistcombinations , thepharmacokineticcharacteristics ofthe antagonistshould be defined fortheintactproductas wellasfor the manipulatedformulation.

Aswithallclinicalstudies,adverseevents shouldbe collected,and thosethat canprovideadditionalinsightabout the abuse-deterrenteffectsare especiallyimportant.For example, ifthemanipulatedformulation is abusedbysnorting, itwould be important to assessadverse eventsrelated to intranasaltolerability.

C.ClinicalAbuse PotentialStudies(Category 3)

Inaddition to their usebyFDA to formulate its schedulingrecommendationunder theCSA fordrugproducts containing a controlledsubstance,clinicalstudies of abuse potential, Category3,are important forassessingtheimpact ofpotentiallyabuse-deterrent properties.Asdiscussed in

9Referencessuggestingthatdrugsassociatedwitharapidonsetofactionareassociatedwithgreaterabusepotentialinclude:

AbreuME,BigelowGE,FleisherL,andWalshSL.2001.Effectofintravenousinjectionspeedonresponsestococaineandhydromorphoneinhumans.Psychopharmacology,154:76-84.

deWitH,BodkerB,andAmbreJ.1992.Rateofincreaseofplasmadruglevelinfluencessubjectiveresponsesinhumans.Psychopharmacology,107:352-358.

deWitH,DidishS,and AmbreJ.1993.Subjectiveandbehavioraleffectsofdiazepamdependonitsrateofonset.Psychopharmacology,112:324-330.

10FDAhasissuedadraftguidanceonthistopic(AssessmentofAbusePotentialofDrugs).Oncefinalized,it willrepresentFDA’scurrentthinkingonthistopic.

FDA’sguidance on thattopic,11the preferred design is a randomized,double-blind,placebo-controlledand positive controlledcrossover study.These studiesgenerallyare conducted in adrug-experienced,recreationaluser population.The useofa pre-qualificationphase (see section2 below) to identifysubjectswhocanreproduciblydistinguish activedrug fromplacebo is acommonenrichment strategyused to improve thepower ofthestudyto establish a differencebetweentreatments.

Additionalconsiderationsapplicable to clinical abuse potentialstudiesused to assess potentiallyabuse-deterrentpropertiesare discussed below.For productsthat arenot susceptible tomanipulationbased on Category1 and 2 testing, studydesignsfor Category3 testingshould bediscussedwithFDA.

1.Blinding

Clinicalstudies of abuse potential should usearandomized, double-blind,placebo-controlledand positive controlledcrossover design.Becausestudysubjects are recreationaldrugusers andfamiliar with the effectsofthedrugsubstances beingstudied, thedouble-dummytechnique orother techniques shouldbe used to ensuretheblindingof alltestswhen possible.However,alternative designsmaybe suitable when theblindingofthestudydrug andthepositive controlcannot be maintainedand treatmentbyperiodinteractionsmaylead to sequenceeffects in acrossover design. Forexample, a paralleldesignmaybe useful when studyingthe intranasalroute of administration,where subjects maybeableto see the differencesin volumeor colorbetweentest drug andplacebo orpositive control,or when it is not possibleto create similarresultsfrommanipulation,suchasparticle sizefrom crushing. Inthese circumstances, earlydiscussionwithFDA is recommended.

For clinicalabuse potential studies in which the subjectswillsnorttestsamples,administrationofthe samples in anarrow neck, opaque containerwith a pre-insertedstrawmayhelp facilitateblinding. However, eventhoughsubjectsmight not be able to see thesample, un-blindingmaystill occur dueto the physicalproperties ofsamples withsimilar particle size distribution.Insome formulations,higher crushedtablet/capsule volumeor larger particle sizemayinhibitcomplete intranasaladministration therebycontributingto the deterrence effects.To beable toevaluate these effects, itmaybenecessaryto maintain differences in tablet/capsule volumebetween thepotentiallyabuse-deterrentformulationand the comparator.Tofacilitate blindingandmaintain the crossover design,placebosmatched to eachofthedifferingweights or particlesizes maybeuseful. Thedetails ofthe preparationofthe samples should beprovided in thestudyprotocol.

2.Pre-qualificationPhase

The purpose ofthe pre-qualificationphase is to increase thepowerofastudyto detectdifferences in theabuse potential ofthe variousformulations of drugandplacebo.12 Ingeneral,